Gram-negative septic shock has received increasing attention in the past decade, but therapy remains empiric and relatively ineffectual. Studies have shown that gram-negative bacterial endotoxin is of primary importance in the development of septic shock. Pathogenetic mechanisms of endotoxemia are incompletely defined, and the lack of understanding of pathophysiology has limited the development of rational therapy. Although species differences in response to endotoxemia exist, vasoactive substances such as bradykinin, histamine and serotonin may be important in all species. Interaction of endotoxin with leucocytes may play a central role in the release or generation of these vasoactive agents. The proposed research will: a) examine the interaction of endotoxin with the leucocytes of several species to define the resultant activation and release of vasoactive agents; b) characterize the enzymatic and amine-storage capabilities of leucocytes of different species, which may determine the primary vasoactive agent released by each species; and c) relate the specific cardiovascular responses observed in different species with the particular vasoactive agents released. In addition, the participation of the early cardiovascular responses of endotoxemia in the outcome of endotoxin shock will be evaluated.